1Department of clinical & Basic Sciences, Research Scientist & Core Member of Research Society of Hubei Polytechnic University, Assistant Professor & Assistant Director, Medical college of Hubei Polytechnic University (HBPU), Huangshi, Hubei PR China
Received Date: April 18, 2019; Accepted Date: May 09, 2019; Published Date: May 17, 2019
Stem cell regenerative medicine is the fastest growing branch of clinical medicine and it has a tremendous role in Orthopedics. All orthopedic surgeries need implants of metal in the form of screws unipolar, bipolar implants, cages, artificial cervical disc, plates etc. After getting these metallic implants, our Bony tissues tend to face Heterotopic ossification and other complications. Problem with hardware implant is that, they can't work exactly as like our own organs & system, for instance hip arthroplasty can't be a substitute for original hip joint & ultimately patients may get decreased or limited mobility in joints & even implant failure might occur. Second problem is that even after successful surgical procedures we need a long time rehabilitation time to mobilise as a normal person. This is why we need regenerative medicine in the field of orthopedics, under which we can regenerate the damaged bone tissue, cartilage, tendon etc.in order to sustain the normal & efficient function of musculoskeletal system. The presented review aims to discuss all the potential benefits of SCRM in Orthopedics.
Stem cell therapy; Stem cell therapy in orthopedics; bone marrow stem cells
BMSCs: Bone Marrow Derived Mesenchymal Stem Cells; MSC: Mesenchymal Stem Cells; OA: Osteoarthritis; PRP: Platelet Rich Plasma; MRI: Magnetic Resonance Imaging; ACL: Anterior Cruciate Ligament; HA: Hydrxyapatite; BMAC: Bone Marrow Aspirates Stem Cell Concentrate
Stem cell regenerative medicine is the fastest emerging branch of medicine - Leland Kaiser introduced the term "Regenerative Medicine" in 1992. He already predicted that a new branch of medicine will develop that attempt to change the course of chronic disease & in many cases it will regenerate the exhausted and failing organ systems . Since then, Scientists around the world are making efforts to develop reverse time therapy to regenerate damaged tissues & organs .
No doubt, scientists have great hopes from regenerative medicine towards orthopedics. They want to develop an alternative regenerative therapy for non-Union, Malunion, large bond defect, or atrophic tendon rupture etc. These are all indications where we are using conventional surgical procedures with implants [3,4]. Problem with hardware implant is that, they can't work exactly as like our own organs and systems, for instance hip arthroplasty can't be a substitute for original hip joint and ultimately patients may get decreased or limited mobility in joints and even implant failure might occur. A Second problem is that even after successful surgical procedures we need a long time rehabilitation time to mobilise as a normal person. This is why we need regenerative medicine in the field of orthopedics, under which we can regenerate the damaged bone tissue, cartilage, tendon etc.in order to sustain the normal & efficient function of musculoskeletal system. Stem cell regenerative medicine is a unique method for treating patients with wide spectrum of diseases & injuries.
The presented review will concentrate on advancement of stem cell regenerative medicine (SCRM) towards orthopedics. Large bone defects & Non Union Cases present a huge therapeutic challenge to the surgeon & these complications put extra financial burden on health care system & society, it is the reason for significant morbidity .
SCRM is a combination of neoosteogenesis & neovascularization, by which we can restore the tissue deficit. This optimal approach includes the knowledge of biomaterial scaffold, cell biology technique, growth factor required for stem cell growth & optimum mechanical environment .
We performed our online search using key word, stem cell therapy in orthopedics, mesenchymal stem cells, avascular necrosis, osteochondral defects, malunion in bones, spinal cord injury, cartilage regeneration, on pubmed, Springer, Google scholar. Full length articles were downloaded directly from pubmed research gate, Google scholar, Springer & other online research portals. After reviewing more than 160 articles, we extracted the clinical data from them to include in our study, which are found relevant and appropriate.
|Author||Diagnosis||Application / number of patients||Outcome|
|Connolly et al.||Atrophic pseudoarthrosis||Percutaneous autologous bone marrow injection/20||Healing capacity comparable to autologous cancellous bone grafting|
|Garg et al.||Non Union in long bones||Percutaneous autologous bone marrow injection/20||17 out of 20 cases shows Union in 5 months|
|Goel et al.||Tibial non-union||Percutaneous autologous bone marrow injection/20||15 out of 20 cases showed bone Union|
|Gangji et al.||Osteonecrosis femoral head||Autologous bone marrow concentrate injected13/18 hips||Pain significantly improved, function also improved significantly|
|Hernigou et al.||Osteonecrosis of femoral head||Autologous bone marrow concentrate injected342(534 hips)||Successful outcome depends on high amount of progenitor cells.|
|Salama & weissman||Different sort of bone defects||Xenografts with bone marrow aspirate/28||Most satisfactory results|
|Marcacci et al.||Large bone diaphysis defect||Autologous MSCs were expanded in vitro& grown with hydroxyapatite scaffolds/4||Follow up till 7 years after surgery, no secondary fractures, and good implant integrations.|
|Hendrich et al.||Bone healing anomalies||Bone marrow concentrate/101||Autogenous bone marrow concentrate applied safely.|
|Giannini et al.||Osteochondral talus defect||Autologous bone marrow aspirate with arthroscopic assisted injection/48||Improvement in functional efficiency.|
|Dallari et al.||High tibial osteotomy||Lyophilised bone chips including platelets-enriched plasma with bone marrow aspirate/33||Study shows Enhanced healing|
|Kitoh et al.||Femoral & tibial lengthenings||In vitro Expanded MSCs applied with PRP/28 (51 osteotomies)||bone healing Not enhanced by MSC/ PRP|
|Wong KL et al.||Knee OA||Cultured autologous BMSCs with hyaluronic acid / 56 knees in 56 patients||Cell recipient group showed remarkable clinical & MRI scores than control group.|
|Intraarticular injection of cultured MSCs can effectively improve short term clinical and MRI outcomes in all recipients.|
|Vangsness et al.||KneeOA||Allogenic BMSCs applied with partial meniscectomy with additional partial meniscectomy/55||Evidence of Meniscus regeneration and knee pain improved following allogenic human mesenchymal stem cell treatment.|
|Wright et al.||Simple bone cyst||Autologous bone marrow aspirate in the form of intra lesional injection/77||Inferior results compared to methyl prednisolone Injection.|
|Park et al.||Simple bone cysts||Implantation of autologous bone marrow aspirate implanted in the combination with non-vital allogenic bone graft or injected with bone powder/20 (23cysts)||Bone marrow - bone powder injection is effective alternative to open treatment.|
|Wakitani et al.||Osteochondral defects in patellofemoral joint||Culture expanded autologousBMSCs with additional collagen gel& autologous periosteum or synovium/3 Pts||After 1 year of transplantation, defect completely covered.|
|Nejadnik et al.||Osteochondral defects||Culture - expanded autologous BMSCs/ knee with additional periosteal flap/ (72 Pts)||Study shows No difference between autologous chondrocyte implantation & BMSC|
|De Windt et al.||Cartilage defect||Allogenic MSCs mixed with 10% or 20% recycled autologous chondrocytes with additional fibrin glue/ 9||At 12 month follow up all patients shows Significant improvement in clinical outcome, histological analysis indicated hyaline like regeneration with high concentration of proteoglycan & type II Collagen.|
|Gobbi et al.||Osteochondral defect in knee||BMAC with additional collagen I /II matrix /15||Final follow up with significant improvement. MRI showed coverage of the lesion with hyaline like tissue in all patients|
|Clarke AW et al.||Patellar tendinopathy||Cultured stem cells got from skin fibroblasts & modulated to grow collagen producing cells/ 46 Pts, 60 patellar tendons||Improvement in function and pain|
|Kim SJ et al.||Improper fracture healing rate / safety||Cultured cells differentiated in to osteoblasts injected with fibrin/ 64 Pts||Fracture healing enhanced safely.|
|Sen RK et al.||Avascular necrosis of head of femur||Uncultured mononuclear cell instillation obtained from bone marrow instilled following core decompression.40 Pts /51 hips||Clinical scores & radiological outcomes become better.|
|Gangji V et al.||Avascular necrosis of head of femur||Uncultured cell instillation obtained from bone marrow & implanted with core decompression /19 Pts/ 24 hips||Improvement in pain & progression to collapse.|
|Dai G et al.||Complete and chronic cervix a spinal cord injury.||Cultured cells transplanted to region surrounding injury 20 cases, 20 control, altogether 40 Pts.||Neurological function improved at 6 months in 10/20 Pts in treatment group|
|Haleem et al.||Cartilage defects of femoral condyles||Culture expanded autologous BMSCs , platelet rich fibrin glue & periosteal flap/ ACL reconstruction & microfracture in 1 patient / total 5 Pts||12 months after transplantation, defect completely filled with complete surface congruity in 3 patients, congruity incomplete in 2 patients.|
|Buda et al.||Osteochondral lesion of knee||Uncultured bone marrow derived stem cells with hyaluronic acid membrane scaffold with platelet rich fibrin./20 pts||No significant improvement as compared to autologous chondrocytes implantation|
|Cristante AF et al.||Chronic spinal cord injury||Uncultured mononuclear cell concentrate obtained from peripheral blood and reinjected by arteriography /39 pts||26/39(66.7%) Pts showed recovery of somatosensory evoked potentials|
|Jäger M et al.||Bone defects because of trauma or Tumor.||Uncultured mononuclear cells obtained from bone marrow aspiration with collagen sponge scaffold/10||Healing of all bones defects|
Table: 1 Application of stem cells in variety of Musculoskeletal Disorders.
SCRM is a fast growing & promising method for a wide variety of Orthopedic diseases and traumatic injuries. In several countries, scientific research about SCRM is promoted by providing more & more funds that's the reason, because of which many quality publications are coming in to light & moreover we are expecting further advanced innovations in the field of SCRM. Human and animals are commonly affected by orthopedic injuries in bone, muscle, tendons, cartilage and so on. Though natural healing power of bone is enough for normal healing process, massive trauma, and aggressive bone tumours can hamper regeneration power of osteogenic stem cells .
Mesenchymal cells (MSCs) have got the ability to develop in to any sort of mesodermal tissue, so that they could be directed to form precursor cells to develop in to several tissues like tendon, ligament, bone, cartilage, muscle. Stem cell regeneration therapy can be used in several conditions . Neen reported that unselected stem cells used with hydroxyapatite (HA) scaffolds had homologous healing rates as autologous grafting & it also prevent donor site morbidity . Bone Marrow aspirates containing stem cells in a ratio of 1:10000 to 1:1,000,000 of nucleated cells have been successfully used to enhance the healing in non-Union cases .
Animal experiments have shown increased proteoglycan content and maintenance of Disc height with percutaneous stem cell injection . Clinical trials are running to explore these results in humans with positive interim results . Effect of MSCs is positive in case of animal studies via intrathecal and local administration; however clinical studies response is mixed . Tamaki reported that muscle derived MSCs involved in regeneration of a crushed peripheral nerve has been done successfully .
Mostly data is based on animal studies showing use of MSCs suitable scaffolds in cartilage healing. Only a few human case studies have been done and shows improved functional outcome after autologous MSCs implantation techniques . Adams reported that stem cells used to treat rat with Achilles' tendon tear treated with stem cell containing sutures have higher failure strength and better histological characteristics . Unselected MSCs were used for ultrasound guided injections in a case series for chronic patellar tendinopathy with good clinical outcomes . Horwitz reported that systemic infusion of allogenic MSCs in six children with osteogenesis imperfecti showed improvement in bone mass & bone growth acceleration . Though the studies showed promise, clear demonstration that the cells involved to the benefits seen in the recipient is still in paucity so these studies are still controversial regarding use of MSCs for osteogenesis imperfecti treatment . Plank showed in a study on pig that MSCs with scaffolds used in physeal defects differentiated in to chondrocytes to give rise to hyaline cartilage & prevents bony bridge formation. Currently there is no clinical study available to support this study .
Another animal study presented by Guan used MSCs modified to express certain surface which enabled them to migrate to the periosteum leading increased bone mass. These methods can be used in the treatment of generalised bone diseases such as osteoporosis . In sum, Table 1 Shows most of the studies are favour of SCRM, and in maximum number of studies showing positive results in osteonecrosis, osteoarthritis, spinal cord injury, fracture healing, patellar tendinopathy, cartilage defect, osteochondral defect, bone cyst, osteochondral talus defect, and non-Union cases. On the other hand in few studies SCRM results are comparable to conventional treatment and Buda  study (2010) stem cell therapy shows No Significant improvement as compared autologous chondrocyte implantation. Above studies also prove the safety of Stem cell regenerative medicine.
The presented review and analysis obviously has its own limitations because we choose limited number of studies. Core weakness of this study is lack of powerful data and heterogeneity of data to reveal the outcome of SCRM in different orthopedic procedure, so we could not compare all outcomes together. Some unidentifiable and hidden factors might be the limitations of our study. Other important studies about SCRM may be missed because of language barrier.
From the above study, it is quite clear that we need more clinical trials to overcome the contradiction between success and failure of SCRM, so that SCRM can be used safely and effectively in orthopedics & other branches of medicine. Last but not the least, because maximum number of clinical trials and animal experimental studies demonstrated the effectiveness of SCRM that's why we strongly suggest that SCRM has got a great potential in Orthopedics.